1. Detección de Déficit A1AT dentro de la población usual con EPOC Robert A. Sandhaus, MD, PhD, FCCP National Jewish Health University of Colorado Alpha-1 Foundation AlphaNet

2. Potential Conflicts Served on advisory boards and/or have presented at events sponsored by: Bayer, Grifols, CSL Behring, AstraZeneca, Baxter, Kamada, Tuteur Receive salary from two not-for-profit organizations that receive industry funding: Alpha-1 Foundation and AlphaNet

3. Outline History of alpha-1 antitrypsin deficiency (AATD) Genetics of A1AT Understanding AATD and its treatment Lessons learned from detection programs

4. 1963 - Alpha 1 -Antitrypsin Deficiency first described 1964 - Role of elastase 1967 - Discovery of neutrophil elastase 1969 - Neonatal cirrhosis 1970s- Cigarette smoke capable of destroying AAT function 1980s- Plasma deficiency due to blockage of release AAT from liver 1987-2010 - Prolastin, Aralast, Zemaira and Glassia approved in US History of AATD

5. Alpha-1 Antitrypsin (A1AT) 52,000 molecular weight protein coded for by single gene on long arm of chromosome 14 Synthesis predominantly in the liver, but also expressed by other cells Transported to blood where it bathes all tissues Prototype SERPIN Primary target: neutrophil elastase Acute phase reactant Anti-inflammatory 52,000 molecular weight protein coded for by single gene on long arm of chromosome 14 Synthesis predominantly in the liver, but also expressed by other cells Transported to blood where it bathes all tissues Prototype SERPIN Primary target: neutrophil elastase Acute phase reactant Anti-inflammatory

6. Genetics of A1AT > 200 mutations of the SERPINA1 gene identified to date – About 1/3 lead to deficiency or dysfunction >100,000 in U.S. with PiZZ, PiZNull, PiSZ >20 million with PiMZ or PiMS Function of as elastase inhibitor persists except in PiF & PiM pittsburg

7. Not Rare? 100,000 with severe deficiency About 5% diagnosed > 95% undiagnosed 15 Million Patients with COPD ~1% have undiagnosed Alpha-1 At least 150,000 with severe deficiency and COPD! (Perhaps as many as 300,000)

8. The “Good” M Phenotype

9. The “Bad” Z Phenotype

10. The Genome and Alpha-1 Co-dominant allelic expression ~ 14,000 base pairs 394 amino acids

11. AATD and disease People with severe deficiency may never get disease Gene by environment interactions play major role Lung disease (emphysema & bronchiectasis) risks factors – Smoking/second hand smoke – Occupational exposures – Frequent lung infections Liver disease (cirrhosis and liver cancer) risk factors – Liver toxins (EtOH, benzenes) – Infection (hepatitis)

12. FEV 1 in Swedish PI ZZ Nonsmokers Piitulainen, Thorax 1997; 53:939

13. Treatment Smoking prevention/cessation! Regular follow-up to detect disease – Reduction of risk factors Usual therapy for lung and liver disease Specific therapy for lung disease exists – Intravenous augmentation of AAT protein – In U.S. indicated for those with severe deficiency and emphysema – Expected to slow progression of lung disease

14. Testing for AATD Alpha-1 Antitrypsin Deficiency is a Laboratory Diagnosis, not a Clinical Diagnosis Why test – Reduce risk factors for disease, treat disease if present – Family counseling and testing

15. Testing methods Blood level of AAT protein – Inexpensive – Often readily available – Good for detecting severe deficiency – Bad for detecting carriers of a single gene Because levels of carriers often in normal range Therefore not recommended for family testing – There are dysfunctional mutations with normal levels Pi-typing – Electrophoretic evaluation of circulating AAT protein – Can detect rare genotypes but not nulls – Interpretation more an art than a science – Expensive

16. Testing methods Genotyping – Logically, should be “gold standard” – Current methodologies rely on PCR probes for most common genotypes (S and Z) – Therefore, will miss rare genotypes and nulls – Becoming quite inexpensive – Highly accurate, especially when accompanied by a level

17. Testing Methods Overall: – When screening for severe deficiency Level testing can be cost-effective – When testing an individual or for family testing Use at least two methods. Always confirm positive results

19. Who to test? ALL PATIENTS WITH DIAGNOSIS OF COPD/EPOC People with a strong family history of chronic obstructive pulmonary disease (COPD/EPOC) People with unexplained liver disease People with precocious COPD/EPOC Adults with asthma with significant fixed airflow obstruction ¿Birth screening/newborn testing?

20. Successes and Failures Most successful testing program thus far: – Family testing Least successful testing program thus far: – Setting up a testing station at a shopping mall Problems with testing all with COPD/EPOC – Prevalence of severe deficiency in COPD ⋍ 1% – Test 100 COPD patients 0 positive results Need to test about 250 with COPD before you’ll find 1

21. ¿Questions?